DESCRIPTION:(Adapted from the application) Systemic arterial hypertension is one of the major causes of morbidity and mortality in the U.S., affecting more than 20 million Americans. At this time the etiology of "essential" hypertension is unknown, although abnormalities in the hormones and transport proteins that regulate "salt handling" appear to be central to the process. A number of studies have demonstrated that activity of the Na/H exchanger is increased in cells of hypertensive individuals and in animal models of genetic hypertension such as the spontaneously hypertensive rat (SHR). During the previous period of grant support (8/91 to present) the investigator has made substantial progress towards understanding the mechanisms that may cause increased Na/H exchange in hypertension. The investigator has cloned the growth factor stimulated Na/H exchanger (termed NHE-1) from rat vascular smooth muscle cells (VSMC), demonstrated stimulation of mRNA expression by growth factors, and found that the dominant mechanism for regulation appeared to be post-transcriptional. Recent studies in his laboratory have identified three proteins that regulate activity of the Na/H exchanger by modifying phosphorylation of specific serine (694 and 703) and threonine residues (696). These proteins are two members of the MAP kinase family (p38 and Big MAP Kinase1 (BMK1)) and the phosphoserine binding protein, 14-3-3beta. The major hypothesis of this continuation proposal is that the alterations in Na/H exchange in hypertension are caused by differences in its phosphorylation state. To prove this hypothesis the following aims are proposed: Aim 1: Characterize the role of p38 kinase in regulating NHE-1 activity in cells from normal and hypertensive animals and patients; Aim 2: Characterize the role of BMK1 in regulating NHE-1 activity in cells from normal and hypertensive animals and patients; and Aim 3: Determine the molecular mechanisms by which 14-3-3beta regulates NHE-1 activity. The proposed research will determine the mechanisms by which phosphorylation of specific amino acids regulates NHE-1 activity. Alterations in the function of p38, BMK1 and 14-3-3beta represent potential mechanisms to explain the universal differences in NHE-1 activity in hypertension, and these proteins may be candidate genes responsible for the hypertensive phenotype.